The lesions seen in the degenerating neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) consist primarily of the TDP-43 protein. How aggregated TDP-43 protein causes neuronal dysfunction and neurodegeneration is poorly understood. However, mutations in the gene encoding TDP-43 cause some forms of familial ALS proving that abnormal TDP-43 causes neurodegeneration. Furthermore, TDP-43 positive pathological lesions appear in postmortem samples from several different neurodegenerative disorders including FTLD-U, ALS, Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies, and Guam amyotrophic lateral sclerosis/Parkinson's dementia. To model TDP-43 neurotoxicity in a simple animal model, we have transgenically expressed human TDP-43 protein in the neurons of the nematode worm, C. elegans. Expression of human TDP-43 in worm neurons causes neuronal dysfunction and accumulation of nuclear inclusions consisting of aggregated insoluble TDP-43 protein. We have previously reported a C. elegans model for the tau pathology seen in human tauopathy disorders including and AD. We propose to use the same methodologies to characterize the new model for TDP-43 proteinopathy with a focus on the mechanisms of TDP-43 mediated neurotoxicity and how the localization of TDP-43 protein alters its toxicity. The neuronal consequences of tau and TDP-43 protein expression will be investigated by profiling the transcriptional and post-translational responses to neurotoxicity. Transcriptional changes will be monitored using an mRNA tagging/microarray hybridization approach to identify genes up-regulated and down-regulated in response to neurotoxicity. The, genetic pathways that normally act to protect against the neurotoxic effects of TDP-43 will be identified using a genome-wide RNAi screening approach. Genes normally required for tau neurotoxicity will also be tested for their ability to modify the neurotoxicity of TDP-43. The long term goal of this work is to develop neuroprotective strategies for neurodegenerative disorders with TPD-43 and tau protein deposits.